Background; Comprehensive analysis by next-generation sequencing has identified oncogenic gene rearrangement of Trk neurotrophin receptors TrkA, TrkB and TrkC (encoded by NTRK1, NTRK2, and NTRK3 gene, respectively) in multiple tumor types including lung adenocarcinoma, colorectal cancer, glioblastoma and acute myeloid leukemia. The creation of gene fusion through genomic rearrangement results in constitutive activation of the kinase domain of Trk. These recent findings encourage study of the therapeutic potential of Trk kinases as drug targets for the specific treatment of patients with oncogenic NTRK gene abnormalities. TAS-119 is a novel small molecular weight inhibitor of Aurora A kinase and currently investigated in phase 1 clinical trial as both an enhancer of microtubule stabilizing drugs and monotherapy (1-3). In addition, TAS-119 shows pan-Trk inhibition with potency similar to Aurora A inhibition. Here, we describe the in vitro and in vivo pharmacologic profile of TAS-119 as a pan-Trk inhibitor.

Methods; Kinase assays were performed with purified recombinant enzymes under optimized conditions using ATP concentration at or just below the respective Km. In cell proliferation studies, cell viability was determined at 72 hour by detecting cellular ATP concentration. Analysis of protein expression including phosphorylated proteins was conducted by Western blotting. In tumor xenograft models, cells were implanted subcutaneously in nude mice. TAS-119 was administered orally with twice daily or intermittent dosing (4 days on/ 3 days off schedule) for 14 days.

Results; TAS-119 inhibited TrkA activity with an IC50 of 1 nM in cell-free system, and inhibited TrkA autophosphorylation and cell proliferation of KM12C colorectal cancer cell line harbouring TPM3-TrkA fusions at sub-nM range. In the KM12C xenograft model, both continuous and intermittent treatment with TAS-119 at 60 mg/kg or 100 mg/kg b.i.d. for 14 days resulted in dose-dependent inhibition of tumor growth with good tolerability. Delays of tumor growth in xenograft model were well correlated with reduction of TrkA autophosphorylation and inhibition of downstream signal transduction like pPLCγ, pERK and pAKT within tumors.

Conclusions; TAS-119 is an orally bioavailable dual-specificity kinase inhibitor developed specifically for both Trk and Aurora A inhibition with favorable profiles in animals. These preclinical data suggest that TAS-119 has therapeutic potential for cancers with Trk rearrangements. Currently, phase 1 dose-escalation clinical trial is ongoing. Although TAS-119 is primarily being developed as an inhibitor for Aurora A kinase, it should also be tested clinically in patients with tumors showing Trk gene rearrangement.

1) 24th EORTC-NCI-AACR Symposium (2012), abstract #251 and #252

2) 25th EORTC-NCI-AACR Symposium (2013), abstract #A268 and #A269

3) 26th EORTC-NCI-AACR Symposium (2014), abstract #P005 and #P178

Citation Format: Hiroshi Sootome, Akihiro Miura, Kimihiro Ito, Takamasa Suzuki, Hiroshi Hirai, Teruhiro Utsugi, Kazuhiko Yonekura. Cross-inhibition of Trk receptors by TAS-119, a novel Aurora A selective inhibitor, exhibits therapeutic potential in a Trk-driven cancer model. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C187.